Combined and differential effects of alpha-thalassemia and HbF-quantitative trait loci in Senegalese hydroxyurea-free children with sickle cell anemia.

BACKGROUND: Our objective was to investigate the combined and differential effects of alpha-thalassemia -3.7 kb deletion and HbF-promoting quantitative trait loci (HbF-QTL) in Senegalese hydroxyurea (HU)-free children and young adults with sickle cell anemia (SCA). PROCEDURE: Steady-state biological parameters and vaso-occlusive crises (VOC) requiring emergency admission were recorded over a 2-year period in 301 children with SCA. The age of the first hospitalized VOC was also recorded. These data were correlated with the alpha-globin and HbF-QTL genotypes. For the latter, three different genetic loci were studied (XmnI, rs7482144; BCL11A, rs1427407; and the HBS1L-MYB region, rs28384513) and a composite score was calculated, ranging from zero (none of these three polymorphisms) to six (all three polymorphisms at the homozygous state). RESULTS: A positive clinical impact of the HbF-QTL score on VOC rate, HbF, leucocytes, and C-reactive protein levels was observed only for patients without alpha-thalassemia deletion. Conversely, combination of homozygous -3.7 kb deletion with three to six HbF-QTL was associated with a higher VOC rate. The age of the first hospitalized VOC was delayed for patients with one or two alpha-thalassemia deletions and at least two HbF-QTL. CONCLUSION: Alpha-thalassemia -3.7 kb deletion and HbF-QTL are modulating factors of SCA clinical severity that interact with each other. They should be studied and interpreted together and not separately, at least in HU-free children.

Effects of Senegal haplotype (Xmn1-rs7412844), alpha-thalassemia (3.7kb HBA1/HBA2 deletion), NPRL3-rs11248850 and BCL11A-rs4671393 variants on sickle cell nephropathy.

OBJECTIVE: Sickle cell anemia (SCA) can cause substantial kidney dysfunction resulting in sickle cell nephropathy, which may be affected by the presence of modifier genes. This study evaluates the effects of some modifier genes on sickle cell nephropathy. METHODS: Patients living with SCA were recruited. Alpha-thalassemia (3.7kb HBA1/HBA2 deletion) was genotyped using gap PCR multiplex. Senegal haplotype (Xmn1-rs7412844), BCL11A-rs4671393 and NPRL3-rs11248850 were genotyped using Mass Array. The effects of variants on kidney dysfunction were then evaluated using multivariate analysis. RESULTS: The number of patients living with SCA included in this study was 162 with a median age of 20 years [minimum-maximum: 4-57] and a female frequency of 53.21%. Senegal haplotype, BCL11A-rs4671393 variant were protective factors against albuminuria stage A2 with an odds ratio (OR) of 0.22 (95% CI 0.05-0.90) and 0.27 (95% CI 0.08-0.96) respectively. The combination NPRL3-rs11248850 variant - 3.7kb HBA1/HBA2 deletion was a protective factor against albuminuria stage A2 (OR = 0.087, 95% Cl 0.01-0.78) but it was a risk factor for glomerular hyperfiltration (OR = 17.69, 95% CI 1.85-169.31). CONCLUSIONS: All four variants displayed a protective effect against albuminuria stage A2. The combination alpha-thalassemia - NPRL3-rs11248850 variant is a risk factor for glomerular hyperfiltration.